BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young
Kensuke Tateishi, Naoki Ikegaya, Naoko Udaka, Jo Sasame, Takahiro Hayashi, Yohei Miyake, Tetsuhiko Okabe, Ryogo Minamimoto, Hidetoshi Murata, Daisuke Utsunomiya, Shoji Yamanaka, Tetsuya Yamamoto
Abstract
Abstract We present a case of a 14-year old boy with tumor-associated refractory epilepsy. Positron emission tomography imaging demonstrated a region with heterogeneous high 11 C-methionine uptake and a region with homogenous low 18 F-fluorodeoxyglucose uptake within the tumor. Histopathological and genomic analyses confirmed the tumor as BRAF V600E-mutated polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Within the high-methionine-uptake region, we observed increased protein levels of L-type amino acid transporter 1 (LAT1), a major transporter of methionine; c-Myc; and constituents of the mitogen-activated protein kinase (MAPK) pathway. We also found that LAT1 expression was linked to the BRAF V600E mutation and subsequent activation of MAPK signaling and c-Myc. Pharmacological and genetic inhibition of the MAPK pathway suppressed c-Myc and LAT1 expression in BRAF V600E-mutated PLNTY and glioblastoma cells. The BRAF inhibitor dabrafenib moderately suppressed cell viability in PLNTY. Collectively, our results indicate that BRAF V600E mutation-activated MAPK signaling and downstream c-Myc induces specific metabolic alterations in PLNTY, and may represent an attractive target in the treatment of the disease.